New research helps explain how cancer evades the immune system

A Dartmouth-led study has shown how cancer evades the immune system, helping it to spread more easily in the body and be more resistant to treatments. The study, featuring contributions from immunology experts and geneticists, was published today in Nature Immunology.

“By demonstrating how a critical pro-cancer mutation enhances tumor growth, our study helps explain how cancers have evolved to produce large numbers of mutations that enable them to evade the body’s defenses and evade treatment, and we may not be able to fight cancer indefinitely,” said co-author Simon Williams, associate professor of immunology and a co-leader of The Dartmouth Institute’s Cancer Center. “There is no known cure, so it is important that we better understand these evasive strategies, which may then help guide future therapies to eliminate cancer cells.”

Researchers believe their work could also have implications for the discovery of therapies to treat cancer in the future, allowing the immune system to better attack tumors and increasing the effectiveness of immunotherapy, a treatment method that uses the body’s immune system to fight cancer.

Previous studies have turned up variations in the cancer genomes that can produce more than doubling G8P8B41 mutations; in particular, a rare mutation that targets the area that cancer cells need to escape immune defences. Another finding, published two years ago in Nature Immunology, has shown that more than 10% of pancreatic cancer cells carry G8P8B41 mutations. In both cases, this variant produces these large mutations and not only has it led to death but also weakens the body’s immune system, increasing the chance that immune-based cancers will gain access to new metastatic sites.

Cancer cells don’t always produce mutations that lead to this large protein mutation—it can occur and cause disruption of normal cell functions. As presented in Nature Immunology, the researchers have now discovered another variant produced predominantly in non-cancerous liver and lung tissue. In liver and lung regions that had not been previously exposed to cancer cells in previous studies, one variant was found between 4.5 and 5 times more common, producing the G8P8B41 mutation.

In Guinea-Bissau type 2 diabetes, patients with the other variant have double the number of mutations reported in the general population. In part of Guinea, where the variant variant mutated and led to severe worms, the situation was similar with gut tumors and kidney cancers.

“In this study by contributing to this research, we can inform the development of new approaches that, by identifying and measuring this related variant in different types of cancer such as cancers of the colon and liver, will enable a better understanding of how cancer cells evade the immune system and further highlight the importance of studying these evasive strategies in order for us to soon attack them with therapy,” said co-author Professor Richard Snodgrass of Dartmouth MIT.

These findings may also have data relevant for understanding calcium channel resistance to the promising stem cell transplantation pilot project at The Dartmouth Institute, in which Dr. Peter Hailey and Dr. Soroc Koserine have seen functional benefit in a subset of leukemia patients after the transplantation of bone or tissue into their tumors.

“Bone marrow transplants initiated at the Institute is currently being investigated for consideration of further attempts to circumvent (anti-tumor immune) cell-mediated immune checkpoint blockade as a viable treatment to treat patients with leukemia,” said Williams.

Co-author the co-leader Dr. Richard Fabian of Vanderbilt University in Nashville, Tenn., who had no relevant financial disclosures.